Excessive intake of vitamin A compounds such as retinoic acid by pregnant animals results in a high degree of embryotoxic response--a fact recently confirmed in human patients with the use of the drug isotretinoin or 13-cis retinoic acid. Since preliminary studies indicate considerable variation between closely related synthetic analogs of vitamin A in the extent of embryotoxic response, we propose an experimental study on a mouse model to explore the mode and site of action of these therapeutic chemicals. The proposal aims to address the following inquiries: (1) Do structural modifications in any of the sites in the vitamin A molecule--such as in hydrocarbon ring, hydrocarbon side chain, or polar terminal group--alter the nature or extent of teratogenesis? (2) Are the differences in embryotoxic activity between analogs explainable on the basis of their pharmacokinetic behavior alone? If not, then (3) what intrinsic biological property is responsible for the teratogenic effects of a retinoid? Since defects in the central nervous system and skeletal tissues predominate in the fetuses exposed to retinoic acid, do these very tissues show stage-dependent variations in the levels of cellular binding proteins? (4) From among a large number of biochemical effects which ensue when embryonic cells encounter hypervitaminosis A, we propose that an initial interference in collagen biosynthesis is the most likely basis for widespread congenital dysmorphogenesis since this ubiquitous protein is needed as supportive framework during all organogenesis. This hypothesis will be tested.